In general, nanoparticles and/or sub-micron (colloidal) particles in the size range of about 10 to about 1000 nm have found use in several applications due to their large surface area among other enhanced engineering properties. These particles are usually produced by wet top-down (size reduction) approaches, or bottom-up (precipitation-based) approaches. Preserving the large surface area and primary size of active nano-particulate agents such as drug substances during wet-phase production and integration into nano-composite micro-particles is generally important.
One issue during the integration step of drying active-loaded nanoparticle suspensions is that nanoparticles typically aggregate and/or agglomerate. This can lead to poor recovery of active (drug) nanoparticles when composite drug-laden micro-particles in various solid dosage forms are re-dispersed in fluids, which in turn can cause loss of surface area and deteriorated active functionality. Incomplete recovery of drug nanoparticles may lead to slow drug dissolution from solid dosage forms and poor drug bioavailability, especially for poorly water-soluble drugs.
In general, the presence of surfactants in formulations has sometimes been found to be important to the recovery of nanoparticles and/or their dissolution. However, in certain applications (e.g., inhalation), surfactants generally cannot be used as they can cause irritation (e.g., to the sensory pulmonary epithelium). In addition, the use of large amounts of surfactants can cause physical instability of drug suspensions through Ostwald ripening and/or agglomeration. Therefore, the development of surfactant-free formulations or formulations with a minimal amount of surfactants is highly desirable.
Dispersants such as sugars (e.g., sucrose, lactose), sugar alcohols (e.g., mannitol, sorbitol), and/or water-soluble polymers (e.g., cellulosic polymer such as HPMC, HPC, PVP, polyvinylalcohol, long chained PEG, etc.) have been added to formulations to enhance drug nanoparticle recovery from the dried nano-composite particles in solid dosage forms. In general, they sometimes allow faster re-dispersion of nanoparticles via enhanced wetting and/or faster matrix dissolution (e.g., wetting/dissolution mechanisms).
In general, particle size engineering is a convenient tool which may be used to control the bioavailability of drugs. Specifically, converting bigger particles into nanoparticles significantly enhances diffusion properties as a result of the large surface area which nanoparticles provide. This knowledge has been used to reduce the particle size of poorly water soluble drugs, via wet stirred media milling (e.g., in such solid dosage forms known as Rapamune©, Emend©, and Tricor©). However, incorporation of nanoparticles into solid dosage forms leads to the loss of their large surface area during drying of nano-suspensions through size growth and/or agglomeration (e.g., forming micro-particles greater than about 1 μm).
The nano-suspensions containing active agents can be dried (e.g., by spray drying, spray freeze drying, freeze drying, etc.), and granulated with or coated on inert excipient particles to convert them into solid dosage forms. During the drying processes, nanoparticles tend to aggregate and form larger particles (sometimes as large as about 1-10 μm particles).
Consequently, the advantages due to the increased surface area via the production of nanoparticles may be lost. These nanoparticle aggregates could be reversible or irreversible depending on the formulation and/or process conditions used during the drying process (see, e.g., Bhakay et al., Recovery of BCS Class II drugs during aqueous redispersion of core-shell type nanocomposite particles produced via fluidized bed coating, Powder Technol., 236, 221-234 (2013)). Moreover, the nanoparticles may not be recovered or released from the solid dosage forms fast and/or completely during the re-dispersion/dissolution, either in vivo or in vitro (see, e.g., Kesisoglou et al., Nanosizing-Oral formulation development and biopharmaceutical evaluation, Adv. Drug Deliv. Rev. 59, 631-644 (2007)).
In some early works, drug nanoparticles were produced by wet media milling in the presence of hydroxypropyl cellulose (HPC) as a stabilizer, followed by spray and vacuum drying, respectively (see, e.g., Lee J, Drug nano-and microparticles processed into solid dosage forms: physical properties, J. Pharm. Sci. 92, 2057-2068 (2003); Choi et al., Effect of polymer molecular weight on nanocomminution of poorly soluble drug, Drug Delivery. 15, 347-353 (2008)). The matrix-type nano-composite micro-particles were re-dispersed in water to check the nanoparticle recovery after drying. During the re-dispersion, nano-composite micro-particles released drug nanoparticles over a period of about 25 hours, and nanoparticle recovery was incomplete in some of this work. Also in this work, the micro-particles formed after vacuum drying could not re-disperse into nanoparticles when dispersed in water, even after stirring followed by sonication.
However, drug nanoparticles have been recovered from nano-composite micro-particles obtained from freeze/convective/vacuum drying containing dispersants (e.g., carageenum, gelatin, and alginic acid), as well as HPC as the stabilizer in the re-dispersion tests using sonication (Kim et al., Effective polymeric dispersants for vacuum, convection and freeze drying of drug nanosuspensions, Int. J. Pharm. 397, 218-224 (2010)).
Nano-suspension samples have been prepared containing the surfactant D-a-tocopherol polyethylene glycol 1000 succinate (TPGS) as the stabilizer by media milling and spray drying them to form nano-composite micro-particles. (Van Eerdenbrugh et al., Drying of crystalline drug nanosuspensions—The importance of surface hydrophobicity on dissolution behavior upon redispersion, Eur. J. Pharm. Sci. 35, 127-135 (2008); Van Eerdenbrugh et al., Alternative matrix formers for nanosuspension solidification: Dissolution performance and X-ray microanalysis as an evaluation tool for powder dispersion, Eur. J. Pharm. Sci. 35, 344-353 (2008)). The drug nanoparticles of these poorly water soluble drugs in this case were not recovered in the dissolution testing.
However, they were recovered when additional dispersants like Avicel®, Aerosil®, Fujicalin® and Inutec® were present in the formulation. Some typical dispersants that are added to formulations to preserve the nanoparticle recovery from the dried nano-composite particles are sugars (e.g. sucrose, lactose), sugar alcohols (e.g. mannitol, sorbitol) and water-soluble polymers (e.g. PVP, polyvinylalcohol, long chained PEG).
The ability to recover the drug nanoparticles from nano-composite particles containing polymer hydroxypropylmethyl cellulose (HPMC) and surfactant sodium dodecyl sulfate (SDS) coated on lactose followed by re-dispersion in water has been shown (see, e.g., Basa et al., Production and in vitro characterization of solid dosage form incorporating drug nanoparticles, Drug Dev. Ind. Pharm. 34, 1209-1218 (2008)).
Similarly, griseofulvin (GE) nanoparticles have been recovered from the core-shell type nano-composite micro-particles containing both HPC and SDS, or SDS alone in the nano-suspension formulation (see, e.g., Bhakay et al., Recovery of BCS Class II drugs during aqueous redispersion of core-shell type nanocomposite particles produced via fluidized bed coating, Powder Technol., 236, 221-234 (2013)). However, GF nanoparticles could not be recovered in the absence of SDS, even though mannitol was added as the dispersant.
It has been observed that it can be difficult to reconstitute surfactant free nanoparticles (Jeong et al., Effect of cryoprotectants on the reconstitution of surfactant-free nanoparticles of poly(DL-lactide-co-glycolide), J. Microencapsulation. 22, 593-601 (2005)). From the above examples, surfactants in general have sometimes been able to re-disperse drug nanoparticles after drying.
As noted, surfactants should be either used sparingly due to their potential negative impact on the physical stability of the nano-suspensions, or attempted to be substantially eliminated completely due to their toxicity especially in inhalation applications (Lebhardt et al., Surfactant-free redispersible nanoparticles in fast-dissolving composite microcarriers for dry-powder inhalation, Eur. J. Pharm. Biopharm. 78, 90-96 (2011); Liversidge et al., Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs, Int. J. Pharm. 125, 91-97 (1995); Liversidge et al., Surface modified drug nanoparticles, U.S. Pat. No. 5,145,684). Therefore, there is a need to develop surfactant-free formulations, or formulations with minimal amount of surfactants.
Superdisintegrants (“SDIs”) have been used in the past to improve the wettability of drugs by co-grinding in planetary mills and/or ball mills (see, e.g., Voinovich et al., Solid state mechanochemical simultaneous activation of the constituents of the silybum marianum phytocomplex with crosslinked polymers, J. Pharm. Sci. 98, 215-228 (2009); Passerini et al., A new approach to enhance oral bioavailability of silybum marianum dry extract: Association of mechanochemical activation and spray congealing, Phytomedicine. 19, 160-168 (2012); Martini et al., Physico-chemical characteristics of steroid-crosslinked polyvinylpyrrolidone coground systems, Int. J. Pharm. 75, 141-146 (1991); Jalali et al., Co-grinding as an approach to enhance dissolution rate of a poorly water-soluble drug (gliclazide), Powder Technol. 197, 150-158 (2010)).
They also have been used to make solid dispersions by dispersing the SDI in a drug solution, followed by evaporation of the solvents via lyophilization, vacuum drying, or drying at room temperature (see, e.g., Srinarong et al., Strongly enhanced dissolution rate of fenofibrate solid dispersion tablets by incorporation of superdisintegrants, Eur. J. Pharm. Biopharm. 73, 154-161 (2009; Carli et al., Influence of polymer characteristics on drug loading into crospovidone, Int. J. Pharm. 33, 115-124 (1986); Williams et al., Disorder and dissolution enhancement: Deposition of ibuprofen on to insoluble polymers, Eur. J. Pharm. Sci. 26, 288-294 (2005); Nokhodchi et al., Preparation of spherical crystal agglomerates of naproxen containing disintegrant for direct tablet making by spherical crystallization technique, AAPS PharmSciTech. 9, 54-59 (2008); Rao et al., Dissolution improvement of simvastatin by surface solid dispersion technology, Dissolution Technol. 6, 27-34 (2010)).
Solid dispersions have been prepared by mixing the drug and SDI in a theta composer, and heating to avoid the use of solvents (see, e.g., Fujii et al., Preparation, characterization, and tableting of a solid dispersion of indomethacin with crospovidone, Int. J. Pharm. 293, 145-153 (2005)). Another way of making solid dispersions is to melt the drug and deposit it on a pre-warmed SDI as carrier (Williams et al., 2005). Commercially available SDIs have particles typically in the size ranges of about 5 to about 100 microns.
SDIs are also commonly incorporated in tablets extra-granularly or intra-granularly (or both) for dissolution improvement. The typical mechanisms are that the SDIs absorb water by their swelling and/or wicking actions, which breaks the tablet matrix leading to a disintegration and release of the drug from tablets (Solis et al., Effect of disintegrants with different hygroscopicity on dissolution of Norfloxacin/Pharmatose DCL 11 tablets, Int. J. Pharm. 216, 127-135 (2001); Zhao et al., The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablets, AAPSPharmSciTech. 6, E120-E126 (2005); Balasumbramanium et al., The influence of superdisintegrant choice on the rate of drug dissolution, Pharm. Tech., 44-49 (2009)).
Thus, an interest exists for improved systems and methods utilizing superdisintegrant-based composite particles for dispersion and/or dissolution of active pharmaceutical agents. These and other inefficiencies and opportunities for improvement are addressed and/or overcome by the assemblies, systems and methods of the present disclosure.